MANHATTAN CRUDE : in an age (and a war) consumed with Purity, the dying Dr Dawson's gift of crowd-sourced 'impure' natural penicillin was not just a global lifesaver. It was also a window into a new way of looking at the world.

Thursday, January 31, 2013

Imagine the Nobel prize winner for medicine , Baron Howard Florey, being pulled off his efforts to discover new antibiotics in the late 1940s by an impatient Leo Fender.

Leo pleads, "Howard,make me a wah pedal, and make it quick ; I need something unique for my new guitar and amp line".

Howard takes his time, and delivers the pedal years late. But it is beautiful finished and has a high fidelity electronic circuit that is so pure that it delivers vanishingly small amounts of harmonic distortion (albeit at the cost of an anemic output).

I can already hear guitar players going "Oh, goody !"

Luckily for humanity, Leo has also telepathed the spirit of penicillin pioneer Henry Dawson back to earth and given him the same assignment.

Early next morning, Henry has the job all done : a crude but workable bread-board design, with screamingly high distortion impurities, but with a low battery drain design and the effect level preset on 11 on a scale of one to ten (aka ("stun").

It is very basic looking , with just one big button, set in the very middle of the sturdy front panel of the wah pedal.

Henry's genius is that this button simply says one word : MORE !

And that my friends, is the essential kernel of the conflict between these two giants of wartime penicillin....

Very early in his investigation of the antibacterial qualities of the liquid beneath a penicillium mold , probably by October 1928, Alexander Fleming came to a truly startling conclusion.

And it is not what you - or he - or any other doctor or scientist might have expected.Finding unknown substances that kill bacteria was and is a commonplace.

Finding a substance that kills bacteria without also killing the patient is a distinct rarity.

But the chances of finding a unknown substance that kills bacteria while (a) not killing the patient AND (b) while being a part of about two dozen other unknown compounds in a bath of 97% water ?

Well, sir, that simply is an event that has mathematic odds well beyond the calculating.

Let us label the Alec Fleming of this startling conclusion, "Fleming I" , because six months later he had - confusingly - become both Fleming I and "Fleming II", depending on his mood.

Fleming II consistently insisted, for the next fifteen years, that penicillin would not become a useful medication until chemists had purified it, discovered its chemical structure and recreated it as an artificial synthetic. Even then, it would only be good as an external antiseptic.

Talk about a parent praising their latest offspring with faint dams !

But while Fleming II's team had actually started down the chemists' path and had produced a much more concentrated (and semi-purified) material, he totally and abruptly abandoned this effort and never wrote it up in his seminal 1929 article.

He never even used this highly concentrated material (a thousand times more concentrated than original his liquid mixture) in any biological experiment.

It could just be that the businessman-bacteriologist Alexander Fleming, a frugal Scot, had more native arithmetic in him than almost all the doctors and scientists who followed him into penicillin - certainly more native arithmetic ability than almost all the writers I have read on the penicillin saga.

Because the two dozen unknown compounds swirling about together hadn't eliminated the anti-bacterial activity or caused a toxic reaction, removing them by purification was a 50/50 shot at improving- or reducing - those two valuable qualities.

In fact, Dawson's co-worker, Gladys Hobby ten long years later was only one of many who were convinced that crude impure penicillin worked better than the equivalent amount of units of pure penicillin did all by itself.

Balancing these unknowns, it wasn't mathematically likely that purifying penicillin 100% was actually going to make it a better medicine.

In fact, since with 1929 levels of original mold juice and the then current state of extraction technology, 100% pure penicillin was probably going to require losing 99% or more of the original anti-bacterial substance, 99 patients would now die so that 1 might receive 100% pure penicillin.

Let me go further, and recall some of the economics lesson professor John Graham taught me too many years ago.

Graham had a way of bringing economic jargon down to ground level, perhaps never more so than in explaining the term "opportunity cost".

I'd like to think that this is the way he'd explain Fleming I's decision to refute Fleming II's progress :

It is not just that purifying the penicillin juice to 100% results in so little penicillin output that 99 potential patients must die so one patient can be treated with 100% penicillin - that has no more medical efficacy than the original un-purified juice.

Because devoting all of your incredible amounts of labour, stress, time, expense, lab space to this purification effort, means your team can't find the time and space to simply produce more absolute units of the original penicillin, with the production technology they already have.

Nor can they find the time, energy and money to improve the biological yield of that original strain of penicillium mold.

In the real world of limited time and resources, when you open one door, you close many others.

Now Fleming II didn't actually go very far down the path of this (pointless) path of purification.

But his team did find success in the much easier and much more potentially useful concentration of penicillin juice ; aka simply removing most of the harmless water, as we do with concentrated orange juice.

If water is the one compound in the mixture known to be harmless, why bother ?

Fleming's strain of penicillium was actually a very potent producer of penicillin on (not in) water : eventually it produced 200 units of activity per ml of liquid in painstaking experiments in the lab, and routinely got at least 40 units in day to day industrial efforts.

But Fleming didn't know how to grow penicillium right to produce its potential in penicillin - and why should be ?

But he also didn't bother to try to find out, from other fungus farmers, how to grow it better.

He was a medical bacteriologist and he grew it as if it was a medically important bacteria.

The results were a disaster : he was lucky to get one unit of activity per ml of liquid.

But even the most careful technique of safely injecting large amounts of liquid by IV drip wasn't going to find a way to get anti-bacterial activity that diluted into the blood stream to cure really life threatening blood poisoning.

Success by this method, as several bold and brave doctors discovered in 1943-1944, wasn't actually that far off : in those early days, even massive infusions of 10 units per ml of liquid would save lives ,and at 40 units per ml of liquid all but the toughest infections could be beat back then.

So if Fleming II concentrated his original liquid down to a thick syrup, he'd have concentrated it enough to inject into patients --- without losing too much of the original scant penicillin in the process OR consuming all his team's limited energy, time and money in the process.

But at this point, another set of experiments convinced Fleming II completely (and totally wrongly) that penicillin would not work at all as a systemic - concentrated, purified or not.

If only he had injected his syrup, mixed with a little bit of saline solution, into a dying mouse, the mouse would lived.

And penicillin would have been in wide clinical use by December 1929, repeating the rapid pattern of Banting's insulin, but this time in spades.

However, Fleming I never put Fleming II's work or conclusions into his 1929 paper - only repeating his conclusions in private conversations , if pushed.

He found, (and so told hundreds of hospital bacteriologists all over the world) , that easy to make, 100% recovery , liquid penicillin worked well as a routine lab clearing agent and for use as an a non-toxic human antiseptic.

Now to October of 1940 , exactly 12 years after Fleming's original startling discovery about 'the non toxicity of impurity'.

Henry Dawson is waiting impatiently for his co-worker Karl Meyer to purify some of Fleming's penicillin up to what the team imagined was the level of purity acceptable to their famous teaching hospital's quality standards.

And to the level they imagined the deliberately vague but purity-obsessed Howard Florey had claimed he had achieved before safely injecting his penicillin into infected mice in the summer of 1940, saving their lives.

Suddenly, while impatiently waiting and pacing the floor, Dawson was presented with a truly Solomon's Dilemma.

He had expected to treat a single patient with SBE, provided the young man didn't die of the invariably fatal disease before Meyer had purified the penicillin to an acceptable level.

Now he suddenly had two young men dying of SBE.

Re-reading Fleming's original article gave him his solution : if purifying merely lent losing half or more (much more) of the limited material available, without making the resulting medicine any less toxic, why bother ?

Merely quickly concentrate the liquid penicillin, so most of the harmless impurities are left in, while the harmless but burdensome excess of water was left out - and you would be quickly left with enough penicillin to treat two patients - and all this could happen before the two men died.

So the spirit of Fleming I , not Fleming II, was guiding Dawson's hand when he injected the world's very first antibiotics , months ahead of schedule, into BOTH Aaron Alston AND Charles Aronson on October 16th 1940.

Fittingly, in this act of inspired charity, Matthew 20:16 was again fulfilled as the Last became the First to receive this healing balm.

(Alston was almost certainly black and Aronson almost certainly Jewish and in 1940s America both were hardly among the truly favoured peoples.)

After Dawson, a few others others would re-read Fleming's paper as if for the first time, and decided to prefer large amounts - today ! - of highly impure but non toxic penicillin, over small amounts of highly purified but no more non toxic penicillin, maybe, tomorrow.

I suspect their grateful patients, plucked back from the grave, more than agreed with their re-reading of Fleming 1929.

Wednesday, January 30, 2013

... a Genie intended to remain secret, military and patented for the duration of the war, until others --- led by Henry Dawson --- fought to set it free to benefit all humanity.

Like the war itself, wartime penicillin was not a single event, as we tend to treat it today, but a six year long, world-wide process - a conflict in fact.

A conflict between the much more powerful and much more numerous Hares, led by Florey, who sought to seal off penicillin in many different senses of that phrase.

The small band of Tortoises , led by Dawson, sought to make penicillin free to mix , again in many different senses of that phrase.

The Hares had all the early running from 1939 till 1944, when the Tortoises suddenly appeared out of the dust , like the US Seventh Cavalry, to save the medical establishment's bacon just moments before the D-Day beaches became red with blood .....

Howard Florey was never more sleazy than in his dealings with Henry Dawson's team, as he desperately fought to restore the family name that his father dis-honored, by trying to remain the sole "hero" of wartime penicillin.

Just try to imagine what an university ethics committee today might say about a professor using his main rival's unpublished paper, sent to him in secret by his close friend (the same government official who censored his rival's paper and forbade its release) to improve his own work that is about to be allowed to be freely published !

That is what full Professor Howard Florey and university vice president and full Professor A N Richards actually did to associate professor chemist Professor Karl Meyer of Dawson's team , in mid 1942.

(As they say, tenure is 'red in tooth and claw'.)The multi-hatted Professor A Newton Richards was a Vice President of the University of Pennsylvania, head of the medical wing of the OSRD , chief consultant to Merck and one of Howard Florey's best friends.

Like Mayor Rob Ford, he also never met a conflict of interest he could resist.

(By contrast, when Norman Heatley met Meyer in January 1942, Heatley recorded that Meyer was willing to send his data to Florey, but Heatley boldly told his boss (Florey) he (Heatley) won't because it didn't seem right, not if Florey was about to publish and Meyer was forbidden to.)

However, Professor Richards was of a very different moral character and saw nothing wrong in sending Professor Meyer's embargoed chemical work on the structure of penicillin to his main academic rival, Professor Florey.

By contrast, Dawson bent over backwards to try and find a source of penicillin for Florey (even at places like Pfizer - a place Florey determinedly didn't want to visit), totally unaware of Florey's well known reputation in the UK for being an academic bush whacker and a magpie of other people's hard work.

Florey's real (if totally private) reason to come to America in 1941, was mainly to establish that he and Merck, not Dawson and Pfizer, was the real leader in the hunt for viable penicillin.

By late 1942, Florey felt sure that the dying Dawson and Pfizer (having joined Merck's cartel) was out of the race.

Sweet indeed then, when in August 1944, a sullen Howard Florey had to stand politely beside Dawson team member Gladys Hobby as she showed him the natural penicillin poring off the Pfizer lines, while Merck and Florey's team at Oxford had totally failed to produce any synthetic penicillin for the D Day beaches.

Florey had spurned both Pfizer and Glaxo, yet it was they who delivered most of the penicillin that landed on the Normandy beaches that day --- "the stone the builders rejected" indeed.

Gladys Hobby saves Howard Florey's own sister -- when he couldn't

Asa series of letters in the Royal Society Archive reveal, in December 1952, Florey had to eat yet more humble pie, first begging and then thanking Hobby for sending her own latest antibiotic off to save the life of his sister (Hilda Gardner) in Australia when his own penicillin wouldn't work....

Monday, January 28, 2013

From early in 1942, American medical journal editors and authors joined scientific journal editors and authors already being "self censored".

Like them, they were asked (virtually required) to submit all articles they were uncertain about, to a NAS/NRC advisory for vetting before printing or submitting.

Supposedly the NAS medical sub-committee was only censored the chemistry of penicillin , but in fact this wasn't consistently imposed until March 1943,when it fell in line with the UK's more legally formal move in this direction.

Between January 1942 till late in 1943, this system's real ambition was to successfully keep every "miracle cure" by penicillin out of medical and scientific media - and thus, by reverse osmosis, out of the daily press.

If the American public didn't hear about this miracle drug, then the chemistry-savvy Germans won't either ---- at least not before D-Day, or so the thought went.

I think the key for this method's success was that the OSRD/CMR/COC controlled (a) all the significant new strains and all the new information on how to make penicillin in mass qualities, (b) controlled all supplies of the resulting therapeutic penicillin (c) and as well was busy dangling $500 million in high-overhead contracts to cash and equipment starved university administrators.

So it could successfully tell the university researchers, commercial penicillin firms and the medical accredited investigators, peep one word and no more penicillin/ penicillin information/ cash.

Informally, the OSRD/CMR/COC tried to fend off all requests for stories on this rumoured new wonder drug from non-science journalists, who they had no hold over.

General reporters also read popular science stories for possible leads, so with none coming forth on penicillin, they actually made very few such requests.

Of course when a *Hearst* *city desk editor* got a *Pulitzer* for *spot news reporting* for saving the life of a baby with the miracle cure penicillin (and modestly reporting the story as well) , all that changed.

(I always thought the real miracle was the Pulitzer Committee giving a prize to a Hearst paper, the arch enemy of George Pulitzer. That and a city desk editor breaking a Pulitzer-worthy foot leather news story without ever leaving his desk (or phone.)

But what I am not sure of , was Byron Price ever asked by the OSRD/CMR's Dr A.N. Richards to amend his codebooks to ask editors to avoid any any mention of penicillin.

I have a request on this out to a real expert on the American experience with self censorship in WWII....

Saturday, January 26, 2013

Just imagine for a moment if Howard Florey had actually done in May 1940 what he claimed he did for the rest of his life.

The one small/simple experiment that Alexander Fleming never did in 1928 and the one small/simple experiment he absolutely needed to do , to become for all time, the fully respected "discoverer" of penicillin.

At least in the eyes of scientists, doctors, historians and knowledgable lay people.

That experiment was to inject some of his mouse juice again into a mouse - but this time a mouse deliberately infected with massive amounts of bacteria, not a healthy mouse.

All to see if his penicillin juice could pricelessly save lives by working internally to root out massive infections, not to merely become another in a long line of antiseptics, to be dabbed on cuts merely as an aid to hurry up their natural scaring and healing.

Fleming never did this experiment.

Crucially, neither did Florey.

Fleming would have to have slowly injected half a gram (cc/ml) of penicillin juice into an acutely ill 20 gram mouse, and since each gram had about 4 units of antibacterial activity in it, that would have been only 2 units of antibacterial activity per dose.

He'd have to repeat this about every 16 hours for perhaps three days to cure the mouse.

By contrast, because Florey first concentrated that penicillin juice down to about one thousandth of its original volume by boiling the water away in a vacuum, he ended up with mere milligrams of a dry brown powder - each mg containing the same antibacterial units as a gram of the original penicillin juice.

But after all this hard work, he also LOST two thirds of the original penicillin activity.

(He'd be fired if he did that for long in a commercial industrial fermentation operation !)

He dissolved 10 of those mgs of dry penicillin powder into .3 cc of distilled water ( back to the future again !) and injected perhaps 20 to 40 units of antibacterial activity into another acutely sick 20 gm mouse, saving its life in one large intense dose.

Luckily his mice did not die of needle fever during that single big dose - Fleming's need to give weaker injections, repeated over a longer period of time, did at least reduce the chance of severe side affects.

Then one half gram of his juice would give the exact same effect as 10 mg of Florey's dried powder (10 units in both cases.)

So an alternative path to Florey's tiresome and loss-inducing concentrating and purifying of tiny amounts of antibacterial activity in the original juice was to fire the team chemist and hire instead an industrial mycologist (fungus fermentation specialist) who knew how to starve a mold into giving more , not less, penicillin !

Up till Florey, all those who had written scientific articles on penicillin had acted as if it would be used as a non-toxic and wholly natural liquid , much as natural liver extracts were used to save those with pernicious anemia.

Florey introduced a totally new - and totally bogus - wrinkle into the effort to put penicillin to work saving lives.

He suddenly claimed that penicillin juice was NOT non-toxic - unknown parts of it was toxic "impurities" and that only the fully pure penicillin was non-toxic.

Though how he knew this, well in advance of getting anywhere near full purification, I best leave to your wild imagination !

Particularly if you knew some healthy person who died suddenly of anaphylactic shock after a routine dose of 100% pure penicillin.

I am afraid I can never forgive Florey for the wasted years and wasted diversion of effort into purifying penicillin juice instead of simply pouring it - NOW ! - into dying patients.....

Fleming didn't share the Nobel prize (for discovering penicillin) for another dozen years.

True --- but he could have got the prize a lot earlier and saved a whole lot of millions of lives in the process , if he had only been a little bit bolder.For almost 40 years, sufferers from invariably fatal (but fortunately relative rare) disease pernicious anemia had been kept alive by a natural substance: liver.

Over time, the amount of natural- raw - liver they had to eat every day fortunately got smaller and smaller and the scientists edged ever closer to defining exactly which little compound it was in liver that kept them alive.

(Vitamin B12).

That happened 28 years after Whipple's initial discovery and about 10 years later after that, it became available as a partially synthesized product.

These three didn't 'wait for the chemists to purify and then synthesize my discovery' before using it to save lives, to use Fleming's words about his discovery.

They richly deserve their Nobel prize.

But if Fleming had only done what Duhig did in 1943 in Brisbane ; ie inject Fleming's 1928 penicillin juice into dying patients, he too might have gotten a Nobel Prize soon after his discovery.

After all, he had stated publicly that his juice, un-touched by chemists' hands - killed deadly bacteria and was harmless to animal or human bodies.

If Fleming had but tested his penicillin juice's possible systemic effects therapeutic effects on even a single mouse, the life saving might have begun in 1928 not in 1943.....

Fleming, in this extremely famous article, defines his "penicillin" as consisting of one or more soluble solid active ingredients in a liquid nutritional broth, no more and no less.

He makes it clear that "penicillin" is merely a useful shorthand for that cumbersome longer phrase.

He never once uses the word impurities or impure or crude: to him his active ingredient is perhaps ALL of the soluble solids left behind when the water is evaporated .Fleming says that this (mixture) of soluble solids and nutritional broth is non-toxic to the extent that it can be injected in a mass of one fortieth of body weight without harm.

(That is, this liquid mixture appears to be safely injectable in a mouse and a rabbit to the equivalent of a single bolus of 1500 to 2000 cc into an average adult human.)

And Fleming isn't the only one never to use impurities or crude in describing penicillin in a scientific report, in the twelve years between 1928 and 1940.

Clutterbuck & Raistrick in 1932 do not use the words impurities or crude, nor does Roger Reid in 1934, or Elizabeth Pickering at Squibb in 1937 or Siegbert Bornstein in 1939.

But Howard Florey, the chemist manque , the anti-clinician, he sure does in 1940.

He might even ask his potential readers, "Purity : how many ways do you want it ?"

Despite being a very short article - almost more of a scientific note in the style of letters to the journal Nature - Florey manages to inject the words "purify" , "not a pure substance", "impure" and "impurities" and talks constantly of his "penicillin preparations" as if they are something quite different and advanced from Fleming's liquid penicillin.

But, in fact, Florey has merely concentrated all the soluble solids by evaporating away the water, so that 4 tiny units of anti-bacterial activity are no longer in a gram of water and solubles, but in a milligram of solubles.

But two thirds of the scarce anti-bacterial activity has been lost in this totally unnecessary and expensive and complex effort : and in any case, this dry powder has to have water added back into it, to inject it for use !

Dawson, Pulvertaft, Duhig, Yermolieva , Berger (among a mere handful of all the world's doctors ---- maybe just .01% of them thought this way) seemed to have picked up on Fleming's crucial point.

A point he quickly missed, because he publicly always said that the substance would have to be synthesized pure by chemists before it might be a useful antiseptic .

But his original point was true, nevertheless.

It was this : that regardless of whatever was the compound(s) with that mixture of soluble solids that had the anti-bacterial powers, the water and other solids had no harmful effect and needn't be laboriously purified out - or even concentrated by evaporation - at a tremendous loss of the anti-bacterial matter.

Dawson is at pains to introduce the word "crude" repeatedly in his 1941 article, but with a much different point that Florey's article a few months earlier.

Dawson wants to hammer home that despite the crudity of this mixture of the anti-bacterial activity and the other soluble solids, it was still non-toxic even when injected ( finally) into the human blood stream : life-saving does not have to wait until the chemist's apple has been polished to a 't' .

Dawson is , in a sense , "The James Lind of Penicillin".

Put in another way, James Lind said we don't know which compound (later determined to be vitamin c) it is in limes that prevents scurvy but that shouldn't stop us from using it - NOW ! - to save lives.

Almost two hundred years later, another Scottish (Canadian) doctor (Henry Dawson) said pretty much the same thing.

The lesson might be this : chemists, let the sleeping dogs of chemical perfection lie ----- while we clinicians get on with saving lives.....

Thursday, January 24, 2013

The American scientific journal "The Journal of Bacteriology" is a top journal in its field, read - at least in peacetime - by workers in that field the world over.

Yet in January 1943, it is revealing that one of the earliest and most persistent researchers as to the chemical structure of penicillin , Karl Meyer, is still free to publish his informed opinion on the formula for penicillin : C14H19NO6 or C14H17NO5 + H2O.

His co-author, clinician Henry Dawson, by way of contrast, is NOT free to reveal that he has achieved a truly spectacular medical event : curing the incurable, invariably fatal SBE with penicillin , still the acid test of all infectious diseases.His first penicillin success with this disease, a young woman known to us only as Miss HH , had just gone home cured - in time for Christmas - just days before Dawson team member Gladys Hobby was due to deliver this paper in Columbus Ohio in late December 1942.

Few members of the January 1943 public, falling by chance upon this journal were likely to care about the chemical formula of a largely unknown new drug - but curing SBE - Oh My, oh my !

Now that was a good news story, with legs.

The OSRD hated good news not of their own making ...

Which is precisely why it was banned ---- and the chemical formula was not.

The very last way the OSRD wanted the public to first hear about penicillin a full year and a half before D-Day, was in the context of a widely publicized civilian miracle cure.

Dropping the miracle-work of D-Day penicillin on a surprised German Army medical corps was not going to work, if the Germans had first heard rumours of miracle cures with penicillin coming from every local American newspaper some two years earlier and had time to grow their own penicillin.

If the price for Dawson continuing to receive penicillin, once his hitherto semi-independent supplier Pfizer joined the OSRD cartel in the Fall of 1942, was to became a OSRD "principal investigator" (aka COC "accredited investigator") then he had to take an extraordinary oath not to reveal anything to anyone, without full OSRD approval.

So nothing public on the success penicillin was having in pulling bodies back from the grave : but if the Germans wished to make penicillin ; well then here is the formula.......

Gloria T Sanders (in her 1986 book on amputations of the lower limbs) mentions in passing that Howard Florey was the first to concentrate penicillin into a solid, so it could finally be used in human therapy.

This has become a commonplace in recent years, as a Google search on "Florey" and "concentrated" will quickly reveal, replacing earlier claims that he was the first to "purify" penicillin.

But since the solid penicillin was in fact not a whit more stable than Fleming's original liquid penicillin, if both were properly stored, it offered no advantages to Fleming's wet stuff and a whole lot of disadvantages.Florey's team had to do a great deal of expensive and labour-intensive chemical work to reduce 3 grams of watery penicillin (containing about 6 to 12 units of biological activity in total) to one milligram of solid penicillin containing about 2 to 4 units in total.

So now, instead of saving three dying patients, only one could be selected to live and the other two had to be triaged to die prematurely.

Remind me again how this was a therapeutic improvement !

And in addition, since life-saving penicillin had to be injected not swallowed, that dry milligram of penicillin had to be dissolved back into three grams of water, to put into the human body.

It seemed a long and wasteful effort, only to end up right back where you began.

The view that anything dried was inevitably better ,"more modern", than its fresh and juicy original was common in the era between the two world wars, particularly in Florey's Britain.

British cooking in the 1920s can be practically defined by the sudden availability year around of abundant and cheap dried fruits from all over the Empire.

Even today, Britain remain far and away the most avid consumers of packaged foods.

But it is not so in medicine that dry is invariably better than wet , along the road of progress.

Unlike penicillin, WWII combat blood goes from dry back to wet ...

WWII started with the military medical services of the Allies happily separating the plasma from the red cells of volunteer blood, throwing away the perfectly good and valuable red cells and then shipping the dried plasma to the combat-front to deal with fatal shock from massive wounds.

Later they realized that while the plasma did prevent immediate death from shock, a badly wounded serviceman who had lots of plasma but not enough red cells was truly over-stressing his already badly stressed heart and lungs needlessly, making survival still touch and go.

So a relatively minor administrative change (providing low tech disposable iceboxes and making liquid blood by plane transport a very top priority) allowed liquid blood to flow to the front-lines in the last year of the war - saving more lives than dry plasma could.

Concentration ,let me remind you, did not separate the tiny amounts ( ppm) of penicillin from the roughly 3% of solute solids (aka impurities) in the original gram of penicillin juice - it merely removed all the (sterile by definition) water.

But since those impurities were basically non-toxic, they were no more (and no less) harmful evaporated temporarily solid or remaining dissolved in water until they were injected.

Dignified, if alpha-male-ish, scientists do not going around saying my penis is longer than yours but they did going around saving my penicillin is purer than yours.

Which is to say, instead of concentrating penicillin purposelessly only to lose two thirds of it, they truly did purify it to a point of being between 15% to 90% pure, but at an even higher cost in terms of chemicals and labour - and penicillin - lost in the process.

But it did not save lives - it cost lives : hardly something those fine folks in Stockholm should be rewarding ....

Wednesday, January 23, 2013

As part of OSRD's campaign to spin its considerable successes and many failures, William College president and historian James Phinney Baxter III was hired in mid war (1943) to assemble a bewitching mixture of hitherto-secret facts and sheer blarney, called "Scientists Against Time".

It sure fooled the 1947 Pulitzer Committee, but it shouldn't continue to fool us.In mid 1943, reports of the consistent creation of crystal pure penicillin began to came in from various laboratories - the final necessary difficult perquisite to beginning the 'easy' chemical synthesis of penicillin.

In what appeared to be a very astute move (at the time!), the OSRD moved to hand off the Congressional blame for the wasting tens of millions of 1940s taxpayers dollars on a failed expansion of biological penicillin production to an inferior Washington bureaucratical competitor (the War Production Board's OPRD).

The OSRD wanted to focus on garnering in all the certain glory coming to the Washington agency that was seen as funding and running the program that led to the synthesis of cheap and abundant artificial penicillin.

But the OSRD lost its gamble.

Instead it was the lowly OPRD that won, in a highly dramatic and timely fashion just in time for D-Day, while high-and-mighty OSRD had to eat millions of taxpayers' dollars spent generating not one nickel of therapeutic synthetic penicillin.

Baxter's job, in the chapter devoted to the OSRD's penicillin efforts, was to spin these awkward facts otherwise.

He was helped by the failure of the underfunded OPRD not to have the money needed to pay for its own tame house historian.

Baxter's job was to convert the biological success of the latecomers OPRD into being just a minor part of the final success of the long time efforts of OSRD-funded chemists to "purify" penicillin.

He sought to tie together the "chemical" ( his words - page 342 of his book) success of in natural penicillin production) as somehow coming out of the 16 years wasted on the "chemical" synthesis of the antibiotic.

The chemical "Purification" of the "crude" mixture of biological penicillin and its biological impurities was to provide that intellectual bridge.

But in fact, the body could care less about purification - it does worry about toxicity, but regards neutral fillers and water as largely irrelevant.

Quite rightly, it only regards the absolute amounts of biological activity (measured in "Units") of soluble penicillin as being important to cure an infection.

It cares not at all about their original relative degree of dryness (concentration), the amount of neutral bulk filler that comes bundled with them, or the amount of water that penicillin comes dissolved in.

After all, the human body is between 50% to 75% water and it quickly dilutes all drugs to incredibly small concentrations.

Now just to remind readers, one gram of water (mass) is one cc (cm3) of water (cubic area) is one ml (volume) --- and a gram of penicillium juice holding 3% of dissolved solids isn't going to fundamentally change this formula much.

James Duhig got 400 to 800 units of biological activity from each one litre flask (containing 200 grams of penicillin liquid) that he grew in his Brisbane lab in 1943-1944, using the exact same strain of penicillium and the exact same low level of technology that Alexander Fleming had in 1928.

That is he got 2 to 4 units per ml/cc/ gm of penicillium medium, the exact same as Fleming got way back in the Fall of 1928.

Basically Duhig and Fleming got about one microgram of active penicillin per gram of water : one part per million, one ppm.

You don't have to be a rocket scientist to know that is not much of a ratio of useful to useless !

But even when Fleming diluted that 1 ppm in a lot more sterile water - down to the level of one part per billion -, a tiny drop of extremely diluted stuff could still kill deadly bacteria.

But Duhig didn't dilute his stuff any further. Instead he chilled his penicillin liquid, only running it through a filter to remove solid solids.

It still contained its 3% of soluble solids "impurities", along with its 97% pure water. It was still as 'crude' as the day it was born.

Then Dr Duhig injected that liquid straight into a woman's blood stream in 300 to 600 gram amounts (aka 300 to 600 ml/cc of solution). (A thousand or two units of biological activity per injection.)

And incredibly (considering that today we would use millions not thousands of units per injection) Duhig's crude penicillin pulled a dying woman almost literally out of her grave.

He finally did in remote Queensland Australia in 1943 what Alexander Fleming in 1928 London - and every single doctor in the world after him - criminally failed to do : use the original penicillin , entirely untouched by the hands of the chemists, to save lives.

But it is another Australian-born doctor, Howard Florey (originally from Adelaide) now operating out of Oxford University, who scientists and historians (including our Dr Baxter) give all the credit for making Fleming's crude "novelty-only" penicillin into a refined/purified life saver, in a famous experiment in May 1940.

But does he - and this famous "mouse" experiment - deserve that credit?

By Florey's own words, he doesn't think so.

And incredibly, Baxter had Florey's actual words in front of him, when he wrote his own account just after the war's end.

Its all there in Florey's second penicillin article, "Further Observations on Penicillin" ,LANCET, August 1941.

(This incredibly detailed article should have been sufficient, in and of itself, for any competent hospital or multinational drug company anywhere in the world of WWII to make life saving penicillin --- provided they could get their hands on Fleming's strain of penicillium, or one like it.)

In this article, Florey does indicate that his March 1941 human therapeutic penicillin has 40 units per mg of powder (page 178).

But on the next page (page 179) he clearly indicates that the powder used in the May 1940 mouse experiment probably had less than 1/10 the biological activity of the current human therapeutic penicillin.

So that powder had 2 to 4 units per mg , compared to the 2 to 4 units per gram of original crude fluid.

That is , we have gone from having penicillin consisting of about one part per million of liquid to consisting one part per thousand of dry powder.

Since all the water is gone, what is in the other 999 parts of that milligram ? Yep, its the same 3% of soluble biological impurities that were in the original crude watery mixture of Fleming.

Florey has not purified his penicillin at all, merely concentrated it (that is merely removed its water ; we make orange or milk powder from their watery originals in the same way, by evaporation).

My essential point is that Fleming's 1928 mixture of natural penicillin and biological impurities was safe to inject, with or without its sterile water being removed.

(And remember, Florey had to put water back into his powder to get it into his patients ; if it was to go in as a slow IV drip, it could be as diluted as it was in the original brew, before all that expensive concentrating.)

That concentration process took not just an awful lot of human energy to perform ; it also destroyed two thirds of the available penicillin.

By late 1942 - early 1943, biological improvements in growing penicillin now gave us raw penicillin brew that gave 40 units per cc of liquid.

The Russians, logically enough, felt there was no need to waste human energy and expensive scarce equipment merely to destroy two thirds of this life-saving liquid, just so they could falsely claim to "purify" it, aka 'concentrate' it.

The other Allies might well have followed their example and then we would have had no mid-war penicillin famine.

Life saving did not require purified penicillin - in fact, the wartime purification of penicillin tended to reduce the amount of penicillin of penicillin available for the dying in figures varying from two thirds to infinity.

Yes infinity : in the Spring of 1943 Glaxo was - briefly - the world's largest penicillin producer.

Incredibly, in the middle of a bloody war, none of that penicillin went to save human lives. It all went to the Glaxo chemists to destroy, trying to get it to go into crystal so they could synthesis it, analogue it and profitably patent it.

Purification, inessential to life-saving, was crucial to the efforts to synthesis penicillin.

Enough penicillin to save millions would have come years earlier if universities and drug companies had released their chemists to the Draft Boards and hired mycologists instead.

But Baxter doesn't play it that way.

Florey had merely evaporated Fleming's penicillin and had thus obtained penicillin that was relatively 1000 times stronger than Fleming.

However, in absolute terms of therapeutic penicillin per flask of penicillin brew, it was actually three times less strong (and remember our bodies and their germs only care about absolute amounts, not relative amounts.)

But Baxter (who wasn't at the experiment) deliberately ignores Florey's own words (and Florey was at the experiment) to confidently and falsely claim that the mouse experiment penicillin was 3% pure.

Actually it was .3% pure , as Florey himself admitted in 1941,the same as Fleming's 1928 crude mixture.

Fleming deserves a lot of credit for making penicillin available - but also a lot of blame as well, when he failed to confirm his failed micro experiment on the possible systemic use of his crude penicillin - by trying it again on a variety of animals and humans.

Florey, similarly, deserved much credit for pushing penicillin to the front of scientific attention - but also a lot of blame for his obsessive need to put make purified crystal penicillin for chemical synthesis.

Worse, he mis-used his scientific authority to actively brow-beated many other decent doctors into stopping their production of "good enough" penicillin, merely to try to save lives in the middle of a savage war.

If they saved lives with crude penicillin, he saw his sole claim to scientific fame disappearing.

Florey readily admitted that he wasn't the first to discover penicillin (Fleming) and tried not to admit that he was not the first to put it into a patient (Dawson) ,but he wanted very much to claim that he was the first to purify it, so it could be injected into humans.

Duhig would dismiss that claim.

As would Dawson, who was at great pains (in his May 1941 article on penicillin) to publicly emphasize that his first human injections were taken from crude, concentrated "not purified, yet non-toxic" penicillin.

Monday, January 21, 2013

For an entire generation of scientists, doctors and science reporters (those working between 1929 and 1949), it was an article of absolute faith that pure penicillin was non-toxic.

But how did they know? How in the hell did they know ?

For during most of those years they had never seen anything like pure penicillin , let alone given it an extensive work-out down in the hospital wards.When the ward doctors finally got their hands on lots of crystal clear 100% pure factory-made penicillin , a not-so-funny thing happened.

Some of the patients got the rigours and the shakes, as some patients had always done on receiving earlier "crude penicillin", but these shakes ended in their sudden and dramatic death from severe anaphylactic shock.

The earlier generation of penicillin researchers (with an extremely tiny handful of exceptions) seemed to stuff logic and reason in the kester, whenever they discussed crude penicillin's non-toxicity.

The evidence before their eyes was clear.

It said, repeatedly, that a crude mixture of one part natural penicillin to thirty thousand parts of its natural impurities and nine hundred and seventy thousand parts water was basically non-toxic, causing only minor and temporary temperature rises when injected into animals (or slightly modified, into humans).

But the mental conclusion they always drew from these visible facts, was logically unwarranted to the max times infinity.

They said - consistently - for twenty years - that pure natural penicillin was extremely non-toxic (it just had to be !) and that the natural impurities were the cause of any fever caused upon injection (it just had to be !)

A lack of undergraduate level logic caused a holocaust of needless deaths

A undergraduate course in Philosophic Logic would suggest that these researchers and science reporters had totally confounded non-toxicity with purity.

Because a logics professor like Rowland C Marshall would remind his students that a moment's reflection should suggest that pure poison is more , not less, toxic than less pure poison : non-toxicity and purity share no relationship.

There are in fact only three possible correct answers in this particular pop quiz :

(A ) The impurities are the sole cause of the temporary allergic fever. (B) The penicillin is the sole cause of the allergic fever. (C) Both can be the cause, varying on the particular set of circumstances and genetic nature of the patients involved.

The truth is, there was no way of knowing, at that time, what was the real cause for this minor temporary fever spike --- particularly after administrating only weak doses of crude mixture 'penicillin'.

A much better test would come when a much stronger doses of pure penicillin were administered and we could see then if strong and pure penicillin doses alone can cause allergic shock or not.

But even that might not convince anybody who felt it just had to be some incredibly tiny fragment from the original natural fermentation process that somehow slipped into 100% pure penicillin and that was the true cause of the allergy.

(A big shout out to Dr Gordon Stewart who pursued this line of thinking, in the true bull-headed cum Sir Robert Robinson fashion.)

Why not, said American chemist John Sheehan, why not wait ?

Why not wait to test an extremely pure dose of synthetic penicillin, which had never ever been near a natural fermentation process, to test it for possible allergy shocks ?

He did so - and finally found that pure chemically synthesized penicillin indeed could still cause allergic reactions in some people.

In the end, it turned out that answer (C) was the correct one , but that with weak doses of penicillin administered fairly slowly, the reaction does not appear to have killed anyone.

At least not before1946 and the issuing of abundant amounts of pure penicillin for use in non-hospital settings.

It not only fooled the generation of idiots who uttered it, it was also the major reason why a whole holocaust of patients died needlessly for 15 years while researchers sought to purify a life-saver that already worked perfectly well in a crude mixture.

To his undying credit, Henry Dawson realized how absurd this thinking was in October 1940 when he said " let's just do it".

He then slipped a needle-full of a crude mixture of natural penicillin and its natural impurities into a patient, confident that the crude mixture would only cause a minor and temporary temperature rise at worst.

His sense of charity and chivalry was admirable, but in this particular case, I would argue his Scottish sense of logic and reason were rarer and more admirable still.....

(a) In the popular imagination, I am often thought of as being a bright yellow powder (though if fact I might often be dark red or brown or even some other color).

(b) Oddly enough, it is exactly the same for me.

(a) Some of my most important developments happened on Manhattan island, with strong Canadian involvement --- I think that was all about the word "Hope".

(b) Wow ! Me ditto,ditto,ditto !(a) The international visual symbol for me is characters in dense black type on a bright yellow background.

(b) That's me too .

(a) A large sample of Americans (men mostly) voted me the top news story of the 20th century for the Newseum.

(b) A large sample of Americans (women mostly) also voted me the top news story of the century for the Newseum.

(a) A little boy is the dramatic climax of my story.

(b) Strange, a baby girl is the dramatic climax of my story as well.

(a) Much of my story happened on a campus at Columbia university and involved Columbia university professors.

(b) So did my story !

(a) I was top secret through most of WWII and I was regarded as one of the best Allied military weapons of the war.

(b) What can I say : ditto ditto .

(a) I am regarded as one of the top scientific discoveries to come out of WWII.

(a) Yeah ? Well so am I .

(a) I was a big project for the OSRD, who spent a fortune on me, until another government agency took me over : but the bosses at the OSRD still kept their hand in.

(b) The OSRD spent quite a bundle on me too - still kept doing so, even after I was taken over by another government agency.

(a) Oh yeah, well I was so important that I was flown all over the world in big bombers.

(b) Bet you weren't flown about as much as me in big bombers.

(a) I was a big deal in Britain : they even act like they invented me.

(b), Oh boy, don't I know that feeling.

(a) The British chemical giant, ICL looked for a while like it would be running me but Vannevar Bush of the OSRD soon stopped that.

(b) And that goes for me too.

(a) In my natural state, I hardly seem to exist, consisting of less than 1% of the natural mix.

(b) I know the feeling, too, actually being much less than 1% of the natural mix.

(a) Well I am so similar to others in the mix, at least in conventional chemical terms, that its a life's work to separate me from them.

(b) That's what all the chemists say about me - usually with a very deep sigh.

(a) I won't work at all, unless I am separated from my natural mix and am about 88% pure.

(b) Now there we finally do differ : because I still work perfectly well even if I am only one part in million of the original natural mix.

(a) There was (and is) a tremendous moral row over whether I should have been built at all but none whatsoever about all the money and effort spent on separating me from my natural mix.

(b) Odd, because while there is no debate at all about whether I should have been built, there is a serious moral debate underway about whether so much scarce wartime energy and resources should have been spent on separating me from my natural mix.

(a) I am considered one of the biggest killing machines in history.

(b) Boy or girl, do we ever part company there : I am one of the smallest lifesavers ever, and one of the best too.

Can you answer this puzzler ?

(a) and (b) So, dear reader : Who am I ? Who am I ?

Answer : (a) the U-235 in the Little Boy Bomb (b) an early vial of Penicillin, who baby Patty Malone and teenagerAnne Shirley Carter helped make an overnight world sensation in August-September 1943 .....

So much has been written about the earliest days of trying to determine the chemical structure of pure penicillin, in such truly massive tomes like "THE CHEMISTRY OF PENICILLIN" and "ANTIBIOTICS,VOLUME II", and much more delightfully in John Sheehan's lucid-but-learned "THE ENCHANTED RING" , that there seems little more to add.

But that is not so, thanks to the South African medical journal SAMJ and its enterprise at putting all of its over 100 years of back issues online and free to access.It is little known that Karl Meyer, the chemist on the tiny pioneering Columbia university team ( the first ever to use penicillin as an antibiotic), contributed an unique intellectual portion to Henry Dawson's first presentation on penicillin.

This presentation was delivered in Atlantic City, at the 33rd annual meeting of the American Society for Clinical Investigation, ( the famous "Young Turks" ) May 5th 1941 --- attended by top medical researchers from all over the world and covered by the scientific and popular media.

To add to the journalistic fun, their more senior and sober counterparts, the American Association of Physicians, met the very next day in the same place - and the two generations of doctors didn't always agree on everything, naturally .

Most penicillin historians seemed to have limited their knowledge of this seminal event to the New York Times report on it, easily available anywhere on microfilm.

But the official abstract of Dawson's presentation , formally published in the Journal of the Society in July 1941, mentions - in passing - two important subject areas that all the popular media left out in describing Dawson's paper.

His presentation talked of the methods of preparation ( and importantly made it clear this took place in Dawson and Meyer's hospital lab and not in some drug company lab), without saying anything more.

Fortunately later articles do amplify on the earliest methods of growing and extraction in great detail.

But the precis also indicates that information as then known of penicillin's chemical nature , ie known as of late 1940-early 1941 , was discussed --- without saying what was speculated.

This speculation is NOT repeated in any later article, because this early speculation was not even close to penicillin's final chemical structure, as found with the help of hundreds of chemists, five long gruelling years later.

But, while I am not a chemist, I think I can say it wasn't a bad guess for what was known - almost by sight and smell - about the earliest dry penicillin powder.

Thanks to SAMJ, the South African Medical Journal

But back to SAMJ - because it was all down to one of their most enterprising correspondents , H O Hofmeyr, that we know anything at all about the earliest chemistry of penicillin.

Hofmeyr came from a very politically powerful Afrikaner family and so it is not surprising he was sent abroad, during WWII, to be South Africa's scientific eyes and ears in places like Washington DC.

He wrote a very complete diary of his visit to the Clinical Investigators annual meeting and it was published, in full ,in the September 1941 monthly issue of SAMJ.

I think I remain the only one to ever cite Hofmeyr's eyewitness report on the opening of the Age of Antibiotics.

I have always treasured his report on Dawson's paper , partly for his slightly snide tone relating that this particular paper caught the imagination of ("sniff") the ("popular") press who gave it ("lurid") headlines like 'Giant Germicide Yielded by Mold'.

But in addition, Dr HO ( as everyone called him) correctly noted in 1941 what current historians always, always miss : that Dawson's use of penicillin on subacute bacterial endocarditis, the dreaded SBE, was in some ways, highly conventional.

Hofmeyr said it still remained in 1941, the absolute "acid test" for the claims of every new potential chemotherapeutic agent.

But buried in middle of the paragraph, Hofmeyr indicates that the Columbia team is willing to speculate publicly that penicillin seems related to the hydroquinones.

The hydroquinones are a big family best known for their use in photo developing and skin whitening, but one in particular, paraquinone ,strikes me as looking, smelling and acting rather like early penicillin powder.

Yellow , arid penetrating smell, very sensitive to acids and bases, yes it sure does look, smell and act like early penicillin.

But paraquinone has only has about one third the molecular weight and number of atoms that penicillin has (and was thought to have in 1941) so it would have to be quite an elaborated version to fit the known facts.

WE have to wait to 1942 and the much better known journals such as NATURE and SCIENCE to find the next set of informed guesses as to penicillin's structural nature, but thanks to SAMJ, we have recovered an important fragment of medical history .....

A nice big fresh juicy orange and a tiny white pill can both have the exact same amount of vitamin c in them : about 100 mg , just above the recommended daily intake of the vitamin for a adult.

The synthetic vitamin c pill (first invented in the 1930s) is of course supposedly pure, but actually consists mostly of "harmless" filler . It is usually taken with a small glass of water.

The orange was - in the eyes of the Modernist 1930s - an impure source of vitamin c. The orange consisted mostly of harmless filler (pulp fibre and a great taste) and about the same amount of water as needed to fill a small glass.Despite being "impure", a whole (100mg) orange a day would actually be more healthy for you than taking half (50 mg) of a "pure" pill every day.

All the body craves is its fix of 100 mg of the "C" a day , not whether human minds consider that vitamin c to be pure or impure.

Unless the vitamin c is bound to something that renders it biologically inactive, the body considers it as fully pure and effective and dismisses what sort of filler and water it chanced to come bundled with.

It was exactly same with the human bodies our two wartime Aussie doctors Duhig and Florey had taken a sacred oath to protect.

Heroic penicillin at its best ...

From twelve one liter flasks growing penicillium fungus in his Brisbane hospital lab , in late 1943, Dr James Dunhig got 2500 cc of penicillin juice, averaging at best five biologically active units of penicillin per cc , or about 12,500 units in total.

This crude, impure, liquid was strained but not processed - only kept chilled.

It was almost immediately put into a 42 year dying mother, a patient of Dr Geaney, in various sizes of IV doses (some as large at 600 cc) over a number of days -- and yet this impure medicine saved her life and home she went to her grateful and astonished family.

Dr Florey,originally from Adelaide, from the same 2500 cc of starting penicillin juice grown in his Oxford university lab in late 1943, also started off with 12,500 units of crude, unprocessed, penicillin.

But he chose to refine it over and over and over and over again, losing and destroying most of the penicillin in the long process.

Finally he ended up with a very little pile of relatively pure powder : one tiny mg of dried penicillin, assaying about 1250 units of biological activity.

But you can't inject dry powder - no matter how pure - into a patient, so some of that oh so expensively extracted water had to be mixed again with the dry penicillin, if it was to be usefully injected in a dying patient.

Non-heroic penicillin, at its worst ...

But it wasn't - it was given instead to chemists, to be deliberately destroyed , all to make a more accurate assessment of penicillin's structure by examining its various sub components.

Then (in the middle of a deadly world war) public domain penicillin could finally - profitably - be synthetically analogued and patented.

Just as well that Florey wasn't moved to waste any of his preciously pure penicillin on a dying woman, because 1250 units of penicillin , no matter how pure, couldn't save most dying adults but 12,500 units of impure penicillin sometimes did.

It is as I say, a classic example of the old saying that 'an whole impure orange a day will keep the doctor away, but half a pill of pure little white pill will not' ...

Two hundred years from now, only the first of the Dawson team's many articles on wartime penicillin will still be cited and still considered seminal.

This, despite the fact that Nova Scotia-born Henry Dawson's last penicillin article told a surprised world that invariable fatal subacute bacterial endocarditis (the much dreaded SBE) had finally been cured - by his penicillin method that he had pioneered 5 years earlier.But instead it is Dawson's first penicillin first article, the "impure but non toxic" article of May 5th 1941, that had (and continues to have) ramifications beyond any one disease, ramifications indeed beyond even medicine and science itself.

In that article, delivered before a large group of international medical researchers in Atlantic City and widely reported by the popular and scientific media from The New York Times to the South Africa Medical Journal, Dawson deliberately paired and then contrasted two oxymoronic phrases.

But first, recall that Dawson chose to appear in front of all his peers to praise his new drug to the heavens AND announce that it had no therapeutic effect on a series of four SBE cases in a row.

Trust me on this one : normally scientists do not rush to the biggest conference in town to proudly announce repeated failure.

But it wasn't the lack of therapeutic success from his impure natural penicillin that Dawson was really so eager to announce.

Rather it was the lack of toxic effects from his crude homemade mixture of natural penicillin and its natural impurities that he was so proud (and perhaps amazed) to announce.

(In a sort of 'reverse Ivory Soap', his starting penicillin brew was far less than 99 and 44 100th percent impure : pure penicillin made up only one part per million of his mixture !)

It could have had - perhaps even should have had - a highly deadly mycotoxin poison buried somewhere in that fungus mix, but God took pity on Humanity and it did not.

We do not have a complete version of Dawson's report and ad lib comments , only various precis. But assembled together, I believe we can garner Dawson's actual words and phrases used to prescribe his main intent behind this article.

He described how his tiny team made their hospital-grown crude (impure) and natural penicillin, calling it both more potent and much less toxic than the factory-made chemically pure synthetic sulfa drugs, less potent and more toxic, made by Big Pharma .

His takeaway line, as the CBC's Don Connolly likes to say, is that "despite being impure, homemade natural penicillin was actually less toxic and much more potent than factory-made pure synthetic sulfa drugs."

"Living better chemically ?"

Today, in this postmodern age, this statement might hardly seem controversial ; but in 1940, at the apogee of Modernity, to diss the Du Pont slogan of "living better chemically" was to indulge in sheer heresy.

At the same university as Dawson (Columbia) and at the exact same time, famed German-scholars-in-exile Adorno and Horkheimer were busy dismantling 500 years of Modernity, brick by brick, and patiently reassembling them as Postmodernity.

Perhaps posthumously, their fellow university colleague Henry Dawson can lay claim to being among Postmodernity's first scientific converts.....

Sunday, January 20, 2013

We have the records of only a few contemporary reactions to Henry Dawson's surprise decision to dramatically kick-start The Age of Antibiotics, 12 years after it should have begun but three months before it was scheduled to begin , but they are suggestive.Gladys Hobby, his assistant, entered the Meyer-Hobby penicillin project a few weeks into it, after taking a late summer vacation.

She returned, she told penicillin author Leonard Bickel just 20 years later, to "an air of excitement filling the Dawson-Meyer lab" , Dawson had "immediately begun to work on this new project" and she "was at once caught up in his eager search".

Dawson was willing to wait "only eight days" after Meyer began purifying his first ever brew of penicillin before, "full of excitement" he injected this just-begun-being-purified material into two dying patients .

One patient died, one went home cured - Dawson refused to credit his small amount of "extremelylow potency" penicillin with this cure, but he was "heartened" by the "low toxicity" of this "extremely crude" preparation. "No serious toxic effects observed."

Hobby later wrote in her own book on penicillin, that Dawson had "recognized immediately that penicillin .... might be effective in the treatment of ...subacute bacterial endocarditis in particular". The product used on October 16th 1940, she admits, was "crude" , "slightly purified (concentrated)" , even "extremely crude" .

At first, only the "low toxicity" of the "crude and impure" penicillin was noteworthy , not its curing ability.

On May 5th 1941, Dawson addressed hundreds of the world's top research doctors in Atlantic City, an event traditionally well covered by the popular media.

So we learn - via the New York Time's famous Atomic Bill Lawrence that Dawson admitted to the audience that despite his "crude" penicillin not being "pure", "no serious toxic effects were observed."

Via science journalist Steven Spencer, writing in America's largest evening paper, the Philadelphia Evening Bulletin, we learn that Dawson said that his penicillin was not toxic even when given in doses far beyond those dosages needed to clear up infections -- a distinct advantage over the sulfas, which are toxic to some people."

He said, reports Spencer, that penicillin had "unlimited possibilities."

Finally, an opponent of Dawson, Stanhope Bayne-Jones tells Howard Florey in strict confidence in July 1941, that Dawson is "quite honest" but "uncriticallyenthusiastic" .

I think I have demonstrated what was Dawson's key insight into penicillin, the insight that drove his excitement and his passion.

It was that he realized that even a crude mix of hospital-made natural penicillin with all its natural impurities still in it was both potent AND non toxic (in fact more potent and much less toxic than drug-company-made PURE sulfa drugs).

So morally, a doctor could not wait for 100% pure natural penicillin or for 100% pure synthetic penicillin, before starting to use penicillin to save the dying by systemic injections.

Before 1945, an entire generation of doctors world wide (except for perhaps a half dozen of them) were more willing to put pure but toxic sulfa or salvarsan drugs into their patients than put impure but non toxic penicillin into them.

I will go further: an entire generation of doctors were willing to seen letting their patients DIE, rather than be seen by other doctors as putting an impure substance into those dying patients.

an obsession with Purity - before even the patients' life

In The Age of Modernity, before 1945, an obsession with purity had its hands tight around the throat of medical morality ....

The real reason why the tortoise Henry Dawson, despite starting almost three years late, beat the hare Howard Florey to become the first ever to put an injection of an antibiotic into a human patient, is to be found inside wartime penicillin's biggest secret.

Unexpectedly, wartime penicillin's biggest secret was not stamped "TOP SECRET" and was not buried under lock and key in some government cabinet in Washington or London.Instead, Henry Dawson discovered it in October 1940, incredibly enough "hidden in plain sight" , on the pages of Alexander Fleming's very first article on penicillin from back in 1929.

Hidden from even its own author for all those years ; remaining hidden to almost everyone ever since - except for a very few caring and observant wartimedoctors.

The great secret is all about non-toxicity and natural penicillin.

No, no , no, ---- don't jump the gun.

Its not that penicillin is non-toxic (because in some crucial ways it is not).

Rather more surprising, the great secret turns on the lucky fact that natural penicillin's natural impurities are so relatively non-toxic.

Fungus are very much a mixed bag on the toxicity front. Lots of them are so non-toxic that we love to eat them as our daily food : bread, beer, cheese, mushrooms, tofu and treated milk products.

Others release tiny amounts of toxins (mycotoxins) so toxic they rate up there with the most deadly poisons we know, by weight.

Back to 1928.

After about ten days of activity, and after a good straining through a lab filter to remove all solids, a gram of Fleming's 1928 penicillium liquid medium contained one part per million of penicillin -- one microgram of penicillin , ie about 1.6 units of bacteria killing activity .

97% of that gram was pure water and the remaining 3% were natural impurities - mostly organic acids.

We humans eat organic acids all the time - particularly in preference to their alkaline opposites, the bases.

Unfortunately, in a the world obsessed with eugenic purity, the good news ended with this particular penicillium strain's thankful lack of general toxicity.

The Age of Modernity liked things to be distinct and separate, not buried together in mixtures : it demanded purity in everything, from the German race to the Allied brand of penicillin.

Unfortunately for this obsession with purity, those various natural acids produced by the penicillium were so much like penicillin chemically (though not at all in anti-bacterial activity) that they were almost impossible to separate from penicillin without either destroying it and or losing it along the way.

In September 1940, at the start of their teaching hospital's first term, Henry Dawson had agreed to restrain his instinct to try and save lives.

Restrain himself, until his fellow team member, chemist Karl Meyer, had purified their penicillin (that the tiny team was home- growing) to a point where it was judged 'pure' enough to inject safely in a human body.

The projected launch date was the start of next school term, in early January 1941: ironically the exact same time Howard Florey's team was scheduled to start injecting their 'purified' penicillin into humans ! Dawson's team didn't know this, how close they came to be 'also-rans' .

Florey thought his team so far ahead he felt no particular urgency to rush into saving lives ; purity and not humanity, was always more his 'thing' anyway.

But ultimately Dawson couldn't stand to stand idly by as two young boys died needlessly from the dreaded and invariably fatal SBE (subacute bacterial endocarditis).

Not when he was convinced that penicillin's unique combination of non-toxicity, potency and diffusibility could save them.

He had not much literature on penicillin to read and re-read while waiting for the difficult process of purification to succeed , not in October 1940: only five articles .

Suddenly he realized that there was a possible solution to his moral dilemma , in that literature and right there under his nose all the time.

All five authors, beginning with Fleming, had mentioned that natural penicillin's natural impurities were not really toxic - at worse, a minor irritant.

So why continue to purify and purify penicillin - at an enormous cost in labour and in penicillin losses?

Why labour to purify it past the point where it could be concentrated (like orange juice), just enough to have a useful therapeutic effect without literally drowning the body in excess water ?

At that time, Dawson team was often making penicillin brew so weak that pouring it directly into a human body (by IV drip) would require putting a kilo of water into the blood stream for every 1000 units of penicillin activity !

But one go around of initial concentration cum purification might result in a little dirty brown powder that assayed 8 units per mg (one thousands of a gram) - 50 mgs of this powder dissolved in a gram of a suitable liquid, 3 times a day, would give the patient 1200 units of penicillin --- without the risk of drowning them internally.

And so on October 16th 1940, Henry Dawson jumped the gun and launched the Age of Antibiotics three months ahead of schedule.

Later on, by mid 1942, the raw penicillin juice made in hospitals assayed at around 40 units per ml of medium (about 25 times as pure) and it no longer needed to be even concentrated like orange juice (because even that resulted in heavy losses and needless additions of chemical contaminants).

It could simply be strained of solids, bottled and stored in a cold dark refrigerator until injected into a patient (and not merely dabbed into the patient's open wound, which was as far as most other penicillin pioneers were willing to go with non drug-company made penicillin.)

This is what a few brave penicillin pioneers (salute their heroic efforts please !) did : Robert Pulvertaft, James Duhig, and Zinaida Yermolieva.

Admittedly ,the first two did save lives by injecting raw penicillin into patients' blood supply, while still expressing some reluctance to do so - by contrast, the soviet team led by Ms Yermolieva did so routinely - all the more praise to them !

An unnecessary penicillin holocaust ...

If only crude raw penicillin had been used to save lives, starting in 1928, millions of people would not have needlessly died world wide , in a totally unnecessary holocaust bigger than anything Hitler had planned for the Jews .....

Saturday, January 19, 2013

If a medicine will save lives when nothing else will do so - in war as in peace - then Henry Dawson's example reminds us that our first moral requirement is to make it as much as we can, anyway we can, save lives anyway we can..... and only then try to perfect it.Fermentation penicillin ( aka natural, biological penicillin) worked (feebly) from day one (September 1928) but could be (and obviously was !) improved gradually.

By contrast, even after 15 years, synthetic penicillin in late 1943 still hadn't been gotten to work at all. (IE, biologically : all resulting attempts showed no medical activity at all.)

In a way , synthetic molecules are completely like pregnancy.

As with pregnancy, there is no half-way house : you are or you aren't ; a synthetic molecule either works, or it doesn't.

In addition, even if synthetic penicillin could be gotten to work biologically, there were still two possible huge problems ahead of breaking out the champagne.

The yield could be much lower than the already low yield of Fleming's original strain of penicillium, not many magnitudes higher.

And the number of steps required in the synthesis and subsequent purification/ separation might require more, not less, money, equipment, manpower, care and close attention to detail than even the worst version of the fermentation method ever called for.

I have one word for you my boy. Rosebud ? No : quinine.

These are not just theoretical objections : as bad luck happens they all came to pass with synthetic penicillin.

The pursuit of synthetic quinine , now a more than two hundred year long futile chasing of a tail by generation after generation of chemists , should have reminded the 1940s penicillin synthetic faithful of the possible pitfalls that could lie ahead......

If pollyanna historians says two years - in the middle of a war - is "soon" , then I guess it must be so."Howard Florey arrives in Peoria in early July 1941 and "soon" planes of the American Air Transport Command are delivering moldy earth samples from the four corners of the world.... and that is why we have abundant penicillin today."

I always knew this story had to be bunk : the Air Transport Command won't even be in the four corners of the world for another year or two or three.

Ken Raper, the man at NRRL who directed that search and should know best says (in the1945 peer reviewed article at the top of this post) that the search started in June 1943.

Ie, after the OSRD stepped back from two years of navel fluff removal and the OPRD got involved in its typically no nonsense way.

If the OSRD's infamous AN Richards wasn't so hell-bound on a chemical synthetic solution, the NRRL would have gotten money and encouragement a lot earlier to search for higher producing strains than those held already by the NRRL --- and these strains were key to the final successful chapter in the long penicillin saga...

A whole lot of people died needlessly of infections that wartime penicillin could have/ should have cured --- all because the Allies decided to treat it as a military weapon of war --- only to be used to cure lightly wounded Allied combat troops, to get them back under enemy fire as soon as possible.Clearly that meant they would rather not have to give penicillin to seriously wounded Allies men or to civilian patients at home or in neutral countries.

In addition, no penicillin for dying civilians in occupied nations or in enemy countries either.

None to enemy troops obviously or to enemy POWs ( though this latter decision was against past custom and current international law.)

But it also meant none for dying Allied POWS behind enemy lines either.

Millions of needless deaths : "The Penicillin Holocaust"

These are just some of the human and moral costs when medical doctors, in their role as government and military advisors, counselled keeping penicillin as a secret weapon of war rather than a public and universal lifesaver.

But one doctor sacrificed his own life to oppose this horrendous policy tooth and nail : Henry Dawson ....

Every Pollyanna account of wartime penicillin has much blather on how (Florey) (Fleming) (you add a name) went to this or that firm asking it to grow some biological penicillin only to find much tea and sympathy but no eagerness to help."The yield is too small, the active ingredient too unstable and too hard to separate from the impurities" ,etc etc.

The accounts then goes on to say, that despite these doubts, the firms did rally around in an international joint effort (cue "The Special relationship" cliche) and today we have cheap, safe, abundant penicillin produced by biological methods.

*The End* (The peasant girl and her prince live happily ever after.)

But while every single firm did, in fact, say those very things about the difficulties of the biological process, they also said a great deal more besides.

Such as : "the chemists are sure to quickly synthesis such a small molecular weight molecule, just as they have with similarly weighted vitamins recently--- so we can't see investing in a full scale biological process, only to see all that money wasted when that plant is immediately replaced by a fast cheap chemical synthetic process."

"So the best we can promise is a small pilot biological plant to produce a little penicillin for experimental treatment of a few patients, with the bulk going to our chemist to determine structure and then synthesis. "

This strong emphasis (right from the very beginning) on giving priority to the chemical synthesis of penicillin rather than an all-out effort to improve the biological yields of the penicillium has been elided out of the good-news story of penicillin.

Partly this is because (a) it failed badly.

But mostly because (b) it delayed for several crucial years the needed research on upping biological yields and (c) prevented the saving of millions dying of wartime infections with the penicillin then-current technology could provide - if governments had wanted it to.

That last point in particular is elided out of existence by the penicillin pollyannas - and rightly so, because what it says about the Allies' behavior on penicillin and the saving of wartime lives is hardly flattering to our cherished collective myths of WWII.....

Howard Florey probably spent no more than a few hours of his whole life in the labs of the NRRL at Peoria, Illinois where most of the fruitful work that gave us the antibiotics revolution was actually done.Within hours, he had dumped his sidekick Norman Heatley there to toil on the rural farmer-like task of growing penicillin, because Florey preferred much more the urban chemistry-oriented approach of firms like Merck and Squibb and ICL.

Florey was no country hick and disdained 'farming' penicillin

Florey after all had wanted to be part of the then most glamorous part of science( chemistry) and only took up medicine as the easiest way for an Australian to get employment in scientific research (as a medical "doctor" , he hated dealing with patients and in fact, hated dealing with people in general.)

He remained a chemist-manque all his life.

Hence why he avoided doing any hands-on research at NRRL Peoria on increasing the biological yield of penicillin .

He much preferred the chemical synthesis approach of Merck and of its chief scientific consultant, A N Richards, new head of the war medicine section of the war weapon research organization, the OSRD....

Read any "Pollyanna" history of wartime penicillin and you quickly garner the impression that wartime Washington's top medical research bureaucrat, AN Richards of the famous OSRD organization, first learned of penicillin when his former student Howard Florey dropped by in the Fall of 1941.

In my opinion : "Bullfeathers" !Richards was the key outside consultant for Merck and had been so since 1931 , so key that he acted more like a trusted insider, rather than playing the traditional role of an external naysayer brought in to correct too much internal group-think.

Since November 1939, a full two years before Richards is traditionally described as first getting involved in "this 'ere pen-E- cil-in stuff", Merck had been working fitfully on trying to learn the structure of public domain natural penicillin with the hope its chemists could produce patentable, profitable "look alike" analogues.

Memo had flown back and forth and committee and board meetings had been called and minutes written.

Hard to believe that Richards the pharmaceutical expert consultant was not consulted formally and informally - ever - during those two years of internal Merck debate on the merits of seriously spending money on synthesizing penicillin.

But the silence from Merck and Richards on just what Richards said to Merck about the potential of penicillin between November 1939 and August 1941 is deafening.

It isn't at all like Richards or Merck to modestly not to claim credit for their early prescience on penicillin.

In fact Merck brass went to enormous length to do just so in the major article "Wartime Industrial Development of Penicillin in the United States", written and researched in the late 1970s (with exclusive access to secret Merck archives) by company senior executiveW H Helfand.

Mysteriously, Richards name is totally absent during this article's discussion of the two years of Merck debate about penicillin, before Florey arrives at Richards' doorstep in Philadelphia.

However Helfand's article quotes Merck executive Osgood Perkins recalling that despite a memo "from so-called experts urging Merck not to waste time on it", in 1940 the company top brass decided to grow penicillin with the aim of isolating its active ingredient.

Now Osgood Perkins was a famous actor of that era but he never worked for Merck.

However the equally famous Wall Street lawyer George W Perkins did - in fact he was the brother-in-law of the company president George W Merck and served as chief operating officer for several decades, including the war years.

(And like his brother in law, Perkins worked at the top of America's highly secret germ warfare program when America formally went to war but still kept a close eye on his company.)

But the quote is from Lennard Bickel's book on Howard Florey, Rise up to Life, and in it, Bickel says he quotes Merck executive Osgood Nichols (also referenced as Osgood Nicholls by Bickel) in conversation with AN Richards in the early 1960s.

(Osgood Nichols probably saw the memos while researching "By Their Fruits" , a book about Merck and Waksman.)

Now I have determined that Bickel did screw up names (but only slightly) in his book, so I feel certain we are looking at Nichols, not Perkins, for the source of this quote.

Richards is silent to Osgood as to who the so called experts might be (and surely he would know) but rushes to defend Florey.

Just exactly how Helfard screws all this so badly is hard to ken.

I suspect that those "so-called experts" included both the much honored Richards and the equally much-honored Columbia university medical researcher, Nobel prize winner and long time Merck consultant Dickinson Richards.

Dickinson worked literally next door to Henry Dawson, who did the most work on penicillin in North America between 1940 and 1941.

So this Dr Richards (no relation to AN Richards) saw the world's then most extensive penicillin efforts (microbiological production, chemical research and clinical efforts with the seriously ill) close up and personal every day.

Thus his opinion on penicillin , as a Merck medical consultant since 1935, between 1940 to 1941 had to be valuable to Merck - but what was it ?

I suspect one of the "the so-called experts" who dissed penicillin was Dickinson Richards.

Why ? Because Helfand does not mention Merck offering to help Dickinson Richards' floor mate Dawson in his penicillin efforts in this very long article tasked with detailing everything and anything positive that Merck had done on penicillin before Florey arrived.

(But we do know what a third outside consultant to Merck said about penicillin because Helfand does quote him extensively.)

Soon to be Nobel Prize winner Selman Waksman is recorded as being strongly in favour of working up penicillin.

I believe that Helfand's job in this article was to recall all the good news and elide any bad news on Merck and penicillin 1939-1941 and he did his job rather well.

I think it would have rather spoiled the seamless panty lines of the traditional "Pollyanna" version of wartime penicillin served up by academic historians, to have revealed that AN Richards knew all about Merck's dilatory efforts with penicillin for two years but did little to speed it along. (And may have even of dissed it.)

Much better is to say that as soon as Florey first told Richards about the wondrous penicillin, Richards leaps into patriotic action to help Britain (cue The Special Relationship) and soon the world has penicillin oozing out of its pores....

Friday, January 18, 2013

There is little morally to fear for all of us agreeing to keep traditional (and temporary) military secrets such as all troop movement before the planned big invasion.By their very nature, such secrets are no longer a secret two or three days into battle.

But Enigma code-breaking, The (atomic) Bomb, the Proximity Fuse and Wartime Penicillin were all military secrets with huge moral costs attached.

Enigma was only kept secret for so long by sometimes deliberately not revealing to the effected military units the grim fate before them that the code-breaking revealed --- all in an attempt to keep the code-breaking secret from the enemy long enough for code-breaking to reveal (and foil) huge plans by the enemy.

This moral dilemma has kept the Enigma industry churning out lots of books and movies, 75 years after the events.

Proximity fuses were so wonderful that we couldn't use them against the Germans, convince they would find one unexploded and quickly duplicate it and then use it to horrible effect against our bomber streams because it was actually more useful to them than to us.

This is the same dilemma that the Germans faced about the nerve gas they invented, because they rightly feared we could make better use of it than they could --- so they never used it and kept it secret.

(At least the Germans didn't put much effort into producing nerve gas because it more or less fell into their laps- while proximity fuses were one of the single biggest scientific and engineering effort of the entire war - in my view, a mammoth mis-allocation of scarce war resources.)

The Atomic Bomb could not remain a 'secret' for very long once it was used, because it was seemingly so war-endingly successfully.

Hence nations big enough to afford it simply felt they had to pour immense amounts of money, expertise and national willpower into duplicating what the Americans had hoped to keep secret for at least a generation.

The entire American civic culture changed, for the worse, when the American atomic establishment decided atomic information could actually be "born secret and kept secret government property", even at the moment a new concept first formed in a scientist's mind !

What really kept the Bomb a 'secret' , quote unquote , is the expense and complexity of making it consistently successfully.

Everyone on Earth had heard of The Bomb, knew what it did , what it was made up and even basically how it worked : the American government had showed them all this in the public Smythe Report.

But a successful Bomb, like the Devil , was in the details ; these were complicated, expensive and remained secret to all but the best foreign spies.

And this - presumably - was how the Allies expected to keep the "Penicillin Secret" once they unleashed it as a secret medicine weapon only for Allied frontline casualties on D-Day (if Patty Malone and that damned beta-lactam ring hadn't spoiled the plan).

Who could really expect to keep the good news about penicillin's life-saving powers away from the general public (aka the relatives of frontline troops), as soon as millions of Allied casualties were coming back home alive, while enemy POWs from the same battle were dying like flies ?

No, like The Bomb, penicillin would quickly become uniquely famous all around the world and only remain a 'secret', quote unquote, because the Allied scientific elite figured that the information as how to make it could remain secret from the enemy for at least a year, because it was complex and expensive.

Remember, even the atomic bomb secret was broken in the end, but only about six years after it became first known to Britain, France and Russia that an A-Bomb would likely work.

That's the length of the entire (long drawn-out) WWII.

So a permanent military secret kept for as short a time as a year long, might still be viewed as long enough to be militarily effective.

But penicillin was no where as complex or as expensive as proximity fuses or nuclear weapons : in fact, it is a piece of cake for every and any hospital bacteriology lab to make safely and cheaply, in amounts sufficient to save the lives of all the people in that hospital dying of infections no other medication could help.

In normal situations, those really are not large numbers, spread over an entire year and over an entire country: in peacetime, there needn't ever be a penicillin crisis, for least for the dying of infections would get it when they really needed it.

But a huge invasion like D-Day requires an extraordinary amount of penicillin over a few days or weeks, in a small area , under fluid combat conditions that obviously doesn't allow much in the way of crude penicillin-making labs in sedate base hospitals.

So war weapon (frontline battle) penicillin really did require a lots of stable penicillin in a dry power, to be useful.

But in fact, even without Patty Malone to tip them off, as soon as word of penicillin great success got about, the enemy would start making it by the crude means known in the vast amount of public literature on penicillin.

But the cost of keeping penicillin a non-public success before unleashing it on D-Day, was in denying it for civilians in Allied,Neutral, Occupied and Enemy countries for years and in fact, in denying it to ordinary soldiers dying of infections penicillin could cure, again between 1940 and 1944.

That is literally millions of needless deaths --- at least as much as the Jewish Holocaust.

It was and is , a horrific moral crime, a deliberate crime promoted by doctors.

And it is why I write about wartime penicillin , 75 years after its events...

About Me

I write, urgently, about our world's painfully too-slow transition into a new era, the Age of Entanglement. Ironically - and typically - this supposed new era actually represents a modified return to the world's oldest philosophy.
For the ancients almost universally saw all life as thoroughly entangled, saw all lifeforms as dining together at a common table - open commensality on a global scale.
Today’s science demonstrates that for us to survive on Earth, humans must sustain the lifeforms that in turn sustain us . So, for example, for us to kill the ocean’s upper reaches will soon remove the very oxygen we need to live.
And economics confirms we can not afford to replace the tens of trillions of dollars of free goods that Nature effortlessly provides humanity annually : there is no “Mars Plan B”.